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Cited by 164Telomeres, Telomerase, and SenescenceT-cell and B-cell ImmunologyRheumatoid Arthritis Research and Therapies

T-cell aging in rheumatoid arthritis

Open access
Weyand, Cornelia M., Yang, Zhen, Goronzy, Jörg J.·2014·Current Opinion in Rheumatology
DOI 10.1097/bor.0000000000000011PMC PMC3984035
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Abstract

PURPOSE OF REVIEW: With progressive age, the immune system and the propensity for abnormal immunity change fundamentally. Individuals greater than 50 years of age are not only more susceptible to infection and cancer, but also at higher risk for chronic inflammation and immune-mediated tissue damage. The process of immunosenescence is accelerated in rheumatoid arthritis (RA). RECENT FINDINGS: Premature T-cell senescence occurs not only in RA, but also has been involved in morbidity and mortality of chronic HIV infection. Senescent cells acquire the 'senescence-associated secretory phenotype', which promotes and sustains tissue inflammation. Molecular mechanisms underlying T-cell aging are beginning to be understood. In addition to the contraction of T-cell diversity because of uneven clonal expansion, senescent T cells have defects in balancing cytoplasmic kinase and phosphatase activities, changing their activation thresholds. Also, leakiness in repairing DNA lesions and uncapped telomeres imposes genomic stress. Age-induced changes in the tissue microenvironment may alter the T-cell responses. SUMMARY: Gain-of-function and loss-of-function in senescent T cells undermine protective immunity and create the conditions for chronic tissue inflammation, a combination typically encountered in RA. Genetic programs involved in T-cell signaling and DNA repair are of high interest in the search for underlying molecular defects.

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Crossref · 10.1097/bor.0000000000000011

Cites

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Claims the paper makes

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  • Premisecitation

    Senescent T cells are phenotypically and functionally distinct from exhausted T cells induced by prolonged antigen stimulation.

    “Based on phenotype and function, senescent T cells must not be confused with exhausted T cells induced by prolonged antigen stimulation [40–42].”
    Quote in the paperSubstantial claim0 of 3 sources checked
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      Not checked in the free run.

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    • cites [42] Akbar AN Henson SM Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat Rev Immunol 2011 11 289 295 21436838 source

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  • Premisecitation

    CD8+CD28− T cells, and to a lesser extent CD4+CD28− T cells, are expanded in chronic CMV infection.

    “CD8+CD28− T cells, and less so CD4+CD28− T cells, are expanded in individuals chronically infected with CMV [27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Turner JE Campbell JP Edwards KM Rudimentary signs of immunosenescence in Cytomegalovirus-seropositive healthy young adults Age (Dordr) 2013 PMC3889879 23846127 source

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  • Premisenone given

    Expansion of CMV-specific T cells produces oligoclonal populations that make up a large fraction of the T cell repertoire.

    “A remarkable finding is that the expansion of CMV-specific T cells leads to oligoclonal populations that comprise a large fraction of the T cell repertoire.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Cellular senescence forces repeatedly replicated cells into permanent cell cycle arrest, limiting the risk of aging-associated cancerous outgrowth.

    “The risk for aging-associated outgrowth of cancerous cells is curbed through the cellular senescence program, which forces cells that have undergone repetitive replications into permanent cell cycle arrest [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Rodier F Campisi J Four faces of cellular senescence J Cell Biol 2011 192 547 556 21321098 PMC3044123 source

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  • Interpretationcitation

    The aging of the immune system is accelerated in patients with rheumatoid arthritis.

    “The process of immunosenescence is accelerated in rheumatoid arthritis.”
    • Also stated in: § Introduction · plain
      “Over the last decade, evidence has accumulated that the immune aging process is accelerated in patients with rheumatoid arthritis (RA) [7–9].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Weyand CM Fujii H Shao L Rejuvenating the immune system in rheumatoid arthritis Nat Rev Rheumatol 2009 5 583 588 19798035 source

      Not checked in the free run.

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    • cites [9] Tarjanyi O Boldizsar F Nemeth P Age-related changes in arthritis susceptibility and severity in a murine model of rheumatoid arthritis Immun Ageing 2009 6 8 19519881 PMC2704168 source

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  • May combine two claims. 33
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Premisecitation

    Human TH17 cells have high self-renewal potential, potent persistence, apoptotic resistance in vivo, and plasticity to convert into other cell types.

    “Human TH17 cells were shown to have a high potential for self-renewal, potent persistence, apoptotic resistance in vivo and plasticity to convert into other cell types.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Kryczek I Zhao E Liu Y Human TH17 cells are long-lived effector memory cells Sci Transl Med 2011 3 104ra100 PMC3345568 21998407 source

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  • May combine two claims.

    Premisecitation

    T cells can reactivate telomerase, elongate telomeres, and thereby extend their life span.

    “In contrast to most other somatic cells, they have the ability to reactivate telomerase, elongate telomeres and thus lengthen their life span [13].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Andrews NP Fujii H Goronzy JJ Telomeres and immunological diseases of aging Gerontology 2010 56 390 403 20016137 PMC2917738 source

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  • May combine two claims.

    Premisecitation

    CD28− T cells produce high levels of IFN-γ, have cytotoxic functions, and accumulate in inflammatory lesions.

    “CD28− T cells are high producers for interferon-γ (IFN-γ), display cytotoxic functions and accumulate in inflammatory lesions [21–26].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [21] Nakajima T Schulte S Warrington KJ T-cell-mediated lysis of endothelial cells in acute coronary syndromes Circulation 2002 105 570 575 11827921 source

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    • cites [23] Liuzzo G Goronzy JJ Yang H Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes Circulation 2000 101 2883 2888 10869258 source

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    • cites [25] Nakajima T Goek O Zhang X De novo expression of killer immunoglobulin-like receptors and signaling proteins regulates the cytotoxic function of CD4 T cells in acute coronary syndromes Circ Res 2003 93 106 113 12816883 source

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    • cites [26] Zhang X Nakajima T Goronzy JJ Tissue trafficking patterns of effector memory CD4+ T cells in rheumatoid arthritis Arthritis Rheum 2005 52 3839 3849 16329093 source

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  • May combine two claims.

    Premisecitation

    The proportion of naïve T cells decreases with age while memory T cell populations increase.

    “As a general rule, the frequency of naïve T cells declines with progressive age and the frequency of memory populations increases (Table 1) [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Arnold CR Wolf J Brunner S Gain and loss of T cell subsets in old age--age-related reshaping of the T cell repertoire J Clin Immunol 2011 31 137 146 21243520 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CMV-specific CD8+ effector memory cells reexpressing CD45RA typically have low avidity and appear to expand mainly in response to antigen-nonspecific cytokine stimulation.

    “A recent study exploring the avidity of CMV-specific CD8+ T cells has demonstrated that CD8+ effector memory cells reexpressing CD45RA typically have low avidity and appear to expand mostly in response to antigen-nonspecific cytokine stimulation [32].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Griffiths SJ Riddell NE Masters J Age-associated increase of low-avidity cytomegalovirus-specific CD8+ T cells that re-express CD45RA J Immunol 2013 190 5363 5372 23636061 PMC3736312 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Premature T cell senescence occurs in chronic HIV infection and contributes to morbidity and mortality.

    “Premature T cell senescence occurs not only in RA, it has also been involved in morbidity and mortality of chronic HIV infection.”
    • Also stated in: § T cell aging in rheumatoid arthritis · plain
      “a similar signature of accelerated immune aging is now recognized in individuals with chronic HIV infection [58**].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58**]

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    Premisecitation

    The gene signature of TH17 cells includes HIF1a and NOTCH, which together regulate survival gene expression.

    “Their typifying gene signature included hypoxia-inducible factor1a and NOTCH which collaboratively regulate expression of survival genes [37].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Kryczek I Zhao E Liu Y Human TH17 cells are long-lived effector memory cells Sci Transl Med 2011 3 104ra100 PMC3345568 21998407 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Defective repair of DNA lesions and uncapped telomeres create genomic stress in aging T cells.

    “Also, leakiness in repairing DNA lesions and uncapped telomeres imposes genomic stress.”
    • Also stated in: § DNA damage-induced immunosenescence in rheumatoid arthritis · hedged
      “Molecular mechanisms causing immune aging in RA are not entirely clarified, but recent studies have shed some light on abnormal genetic and biochemical pathways relevant in T cell senescence (Figure 2) [62,63].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [62] Cavanagh MM Weyand CM Goronzy JJ Chronic inflammation and aging: DNA damage tips the balance Curr Opin Immunol 2012 24 488 493 22565047 PMC3423478 source

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    • cites [63] Georgin-Lavialle S Aouba A Mouthon L The telomere/telomerase system in autoimmune and systemic immune-mediated diseases Autoimmun Rev 2010 9 646 651 20435169 source

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  • May combine two claims.

    Premisecitation

    In elderly humans, sustained induction of NF-κB target genes is defective, suggesting impaired inflammatory responses, yet some NF-κB target genes including IL-1 and IL-6 remain persistently upregulated even without NF-κB triggering.

    “The human response pattern included a defect in the sustained inducibility of NF-κB target genes in the elderly, suggesting a defect in mounting inflammatory responses. However, this defect was combined with persistent upregulation of a subset of NF-κB target genes, including IL-1 and IL-6, even in the absence of NF-κB triggering.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Bektas A Zhang Y Wood WH 3rd Age-associated alterations in inducible gene transcription in human CD4+ T lymphocytes Aging (Albany NY) 2013 5 18 36 23385138 PMC3616229 source

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  • May combine two claims.

    Premisenone given

    CD28− T cell populations are oligoclonal; CD4+CD28− cells are relatively resistant to apoptosis, while CD8+CD28− cells are more likely to die in vitro.

    “These T cell populations are oligoclonal; CD4+CD28− T cells are relatively apoptosis resistant, whereas CD8+CD28− T cells are more likely to die, at least in vitro.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The aging immune system impairs protection against malignant cells and pathogens but increases the risk of autoimmunity and is linked to chronic inflammation.

    “The aging of the immune system impairs protective immunity against malignant cells and pathogens, but paradoxically increases the risk for autoimmunity and goes hand-in-hand with a state of smoldering chronic inflammation [5,6]*.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5,6]*

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    Premisecitation

    Deletion of p16(INK4a) in T cells counteracts several aging phenotypes, including thymic involution, reduced release of naïve T cells, and weakened antigen-specific immune responses.

    “Deletion of p16(INK4a) in T cells has been effective in counteracting several aging phenotypes, such as thymic involution, decreased release of naïve T cells, and attenuation of antigen-specific immune responses.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Liu Y Johnson SM Fedoriw Y Expression of p16(INK4a) prevents cancer and promotes aging in lymphocytes Blood 2011 117 3257 3267 21245485 PMC3069667 source

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  • May combine two claims.

    Premisecitation

    CD8+CD28− T cells regularly accompany aging, whereas CD4+CD28− T cells are usually present at lower frequencies.

    “CD8+CD28− T cells regularly accompany the aging process, whereas CD4+CD28− T cells are typically present at lower frequencies.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Chou JP Effros RB T cell replicative senescence in human aging Curr Pharm Des 2013 19 1680 1698 23061726 PMC3749774

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    • cites [20] Broux B Markovic-Plese S Stinissen P Pathogenic features of CD4+CD28- T cells in immune disorders Trends Mol Med 2012 18 446 453 22784556 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Age-related changes in the tissue microenvironment can alter T cell responses.

    “Age-induced changes in the tissue microenvironment may alter T cell responses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Exhausted T cells express TIM-3, PD-1, and LAG-3, while human senescent cells express KLRG1, ILT2, and varying KIR family members.

    “The phenotypic signature of exhausted T cells includes TIM-3, PD-1 and LAG-3, whereas human senescent cells express KLRG1, ILT2 and varying members of the KIR family.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    IFN-γ and TNF-α released by senescent T cells drive cancerous cells into senescence and are ultimately host-protective.

    “recent data showing that IFN-γ and TNF-α, two classical proinflammatory cytokines that are released by senescent T cells, drive cancerous cells into senescence and thus are ultimately host-protective [36]*.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36]*

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  • May combine two claims.

    Interpretationreasoning

    Gain- and loss-of-function changes in senescent T cells weaken protective immunity and create conditions for chronic tissue inflammation, a combination often seen in RA.

    “Gain- and loss-of-function in senescent T cells undermine protective immunity and create the conditions for chronic tissue inflammation, a combination typically encountered in RA.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Secreted products of senescent cells have been linked to tissue repair but are mostly active in damaging aging tissue sites by sustaining persistent inflammation.

    “Products secreted by senescent cells have been implicated in tissue repair, but are mostly active in damaging aging tissue sites through sustaining a persistent inflammatory reaction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Telomerase upregulation is defective in RA patients, which shortens T cell longevity.

    “This mechanism of telomerase upregulation is defective in patients with RA, shortening the longevity of T cells [14].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Fujii H Shao L Colmegna I Telomerase insufficiency in rheumatoid arthritis Proc Natl Acad Sci U S A 2009 106 4360 4365 19255426 PMC2657451 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    T cells are especially vulnerable to aging because they undergo massive proliferative stress, have long life spans as memory carriers, and depend on thymic intactness for repopulation.

    “Three determinants make T cells explicitly susceptible to aging: (1) enormous proliferative stress, as they have to clonally expand massively with antigen exposure; (2) long life span as the carriers of immune memory; and (3) dependence on thymic intactness for repopulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    These data challenge memory expansion as the main process skewing the T cell repertoire and shift attention to the proinflammatory cytokine environment in the aging host.

    “These data question memory expansion as the lead process skewing the T cell repertoire and refocus attention to the proinflammatory cytokine milieu in the aging host.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ataxia telangiectasia results from a mutation in the ATM DNA damage sensing kinase.

    “One of the aging syndromes, ataxia telangiectasia (AT), results from a genetic defect in the DNA damage sensing kinase ataxia telangiectasia mutated (ATM) [72,73].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [72] Reynolds JJ Stewart GS A nervous predisposition to unrepaired DNA double strand breaks DNA Repair (Amst) 2013 12 588 599 23684796 source

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    • cites [73] Anheim M Tranchant C Koenig M The autosomal recessive cerebellar ataxias N Engl J Med 2012 366 636 646 22335741 source

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    • Rests on an assumption: Many progeroid syndromes are nuclear instability syndromes caused by mutations in DNA repair molecules.

  • May combine two claims.

    Premisecitation

    T cells from rheumatoid arthritis patients are ATM-deficient, accumulate DNA breaks, and fail to repair radiation-induced DNA lesions efficiently.

    “Patients with RA have ATM-deficient T cells which accumulate DNA breaks and fail to efficiently repair radiation-induced DNA lesions [74].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Shao L Fujii H Colmegna I Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis J Exp Med 2009 206 1435 1449 19451263 PMC2715066 source

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    • Rests on an assumption: Cells have effective machinery for recognizing and repairing DNA damage.

  • May combine two claims.

    Premisecitation

    Recent studies found that rheumatoid arthritis T cells lack the glycolytic enzyme phosphofructokinase-2, which causes metabolic rewiring and lower intracellular energy production.

    “Recent studies have identified a deficiency of the glycolytic enzyme phosphofructokinase-2 in RA T cells, causing metabolic rewiring and reduced intracellular energy generation [77**].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77**]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    HIV T cells show insufficient telomeric repair because of abnormalities in the shelterin protein complex, which leaves chromosomal ends exposed.

    “Insufficient telomeric repair has also been reported for HIV T cells due to abnormalities in the telomeric protection complex of the shelterin proteins, thereby leaving chromosomal ends exposed [70]*.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70]*

      Not checked in the free run.

    • Rests on an assumption: DNA replication is inefficient at chromosomal ends, so replicative stress causes telomeric sequence loss.

  • May combine two claims.

    Premisecitation

    CD4 T cells from RA patients have dysregulated signaling cascades that shift their threshold to activating signals and may remove them from protective tolerance mechanisms.

    “CD4 T cells from RA patients are characterized by dysregulated signaling cascades, shifting their threshold to activating signals and possibly removing them from protective tolerance mechanisms [51**].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51**]

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  • May combine two claims.

    Interpretationnone given

    Immunosenescence results in reduced protective immunity together with excessive inflammatory activity.

    “The process of immunosenescence leads to declining protective immunity combined with excessive inflammatory activity.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: DNA replication is inefficient at chromosomal ends, so replicative stress causes telomeric sequence loss.

  • May combine two claims.

    Interpretationreasoning

    Ongoing repair activity causes cellular stress via the DNA-PKcs-JNK axis, which may alter T cell function and push them toward excessive inflammatory activity.

    “Chronic repair activity imposes cellular stress through the DNA-PKcs-JNK-axis, possibly skewing the functionality of T cells and biasing them towards excessive inflammatory activity.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: DNA breaks or chemical modifications can cause mutations and eventually malignant cell growth.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    HIV infection accelerates aging, and illnesses typical of the elderly are highly frequent among HIV-infected individuals even when therapy suppresses the virus below detection limits.

    “There is an emerging consensus in the scientific community that HIV infection hastens the process of aging and that illnesses that appear typically in the elderly are highly frequent among HIV-infected individuals, even in those with therapy-induced suppression of the virus below detection limits [59,60].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [59] Lohse N Hansen AB Pedersen G Survival of persons with and without HIV infection in Denmark, 1995–2005 Ann Intern Med 2007 146 87 95 17227932 source

      Not checked in the free run.

    • cites [60] Losina E Schackman BR Sadownik SN Racial and sex disparities in life expectancy losses among HIV-infected persons in the united states: impact of risk behavior, late initiation, and early discontinuation of antiretroviral therapy Clin Infect Dis 2009 49 1570 1578 19845472 PMC2783631 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Premature immune aging occurs in rheumatoid arthritis, chronic HIV infection, and progeroid syndromes, and these conditions share early age-associated comorbidities such as cardiovascular disease and metabolic syndrome.

    “Prematurity of the immune aging process has been described in rheumatoid arthritis, in chronic HIV infection and in the progeroid syndromes, all of which are characterized by the early development of age-associated comorbidities, such as cardiovascular disease and metabolic syndrome.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: DNA replication is inefficient at chromosomal ends, so replicative stress causes telomeric sequence loss.
    • Rests on an assumption: Many progeroid syndromes are nuclear instability syndromes caused by mutations in DNA repair molecules.

  • May combine two claims.

    Premisecitation

    Signifying abnormalities in RA T cells, including premature telomere loss, extend to CD34+ hematopoietic progenitor cells, separating antigen recognition from cellular aging.

    “Also, the signifying abnormalities in RA T cells, including the premature loss of telomeres, have been extended to CD34+ hematopoietic progenitor cells, separating antigen recognition and cellular aging [64,65].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [64] Colmegna I Diaz-Borjon A Fujii H Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis Arthritis Rheum 2008 58 990 1000 18383391 PMC2820283 source

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    • cites [65] Colmegna I Weyand CM Haematopoietic stem and progenitor cells in rheumatoid arthritis Rheumatology (Oxford) 2011 50 252 260 20837497 PMC3021951 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Complete viral suppression in HIV infection does not protect the host from immunosenescence.

    “A similar dilemma exists in HIV infection, where complete viral suppression fails to protect the host from immunosenescence.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CD4 T cells from elderly donors have signaling inhibition due to overexpression of DUSP4, which impairs T-cell dependent B cell responses.

    “Specifically, CD4 T cells from elderly donors suffer from signaling inhibition due to overexpression of the nuclear dual specific phosphatase 4 (DUSP4) [49]*, impairing T-cell dependent B cell responses.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49]*

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased p16(INK4a) expression in T cells of HIV-infected subjects and an inverse relationship with therapy-induced CD4 T cell recovery suggest p16 as a possible biomarker of T cell aging.

    “Increased expression of p16(INK4a) in T cells of HIV-infected subjects and an inverse relationship between p16(INKp4a) expression and therapy-induced CD4 T cells recovery has suggested a possible role of this senescence-associated gene as a biomarker of T cell aging [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Nelson JA Krishnamurthy J Menezes P Expression of p16(INK4a) as a biomarker of T-cell aging in HIV-infected patients prior to and during antiretroviral therapy Aging Cell 2012 11 916 918 22738669 PMC3697001 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Comet assay tail lengths are elevated in rheumatoid arthritis cells from patients with active and inactive disease, indicating a complex relationship between inflammation and the DNA repair defect.

    “Elevated tail length measurements in comet assays of RA cells have been reported in patients with active and inactive disease, suggesting a complicated relationship exists between the inflammatory milieu and the DNA repair defect [75].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Karaman A Binici DN Melikoglu MA Comet assay and analysis of micronucleus formation in patients with rheumatoid arthritis Mutat Res 2011 721 1 5 21256244 source

      Not checked in the free run.

    • Rests on an assumption: Cells have effective machinery for recognizing and repairing DNA damage.

  • May combine two claims.

    Interpretationnone given

    The mechanisms of T cell aging include reduced T cell diversity from uneven clonal expansion, altered T cell signaling that favors phosphatase activity, and defects in DNA damage and telomere repair.

    “Mechanisms underlying T cell aging are beginning to be understood and encompass contraction of T cell diversity due to uneven clonal expansion, rewiring of the T cell signaling apparatus favoring phosphatase activity and defects in DNA damage and telomere repair.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: DNA replication is inefficient at chromosomal ends, so replicative stress causes telomeric sequence loss.
    • Rests on an assumption: T cells can increase telomerase activity to extend their telomeric reserve.
    • Rests on an assumption: Cells have effective machinery for recognizing and repairing DNA damage.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Progeroid syndromes have provided important clues about the causative abnormalities underlying immunosenescence.

    “Such progeroid syndromes have provided important clues as to the causative abnormalities underlying the immunosenescence process [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Reinhardt HC Schumacher B The p53 network: cellular and systemic DNA damage responses in aging and cancer Trends Genet 2012 28 128 136 22265392 PMC4120491 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A 20-year-old adult starting ART may have already lost one-third of remaining life expectancy.

    “It has been estimated that a 20 year-old adult initiating ART may already have lost one-third of the remaining life expectancy [61].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies Lancet 2008 372 293 299 18657708 PMC3130543 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The presence of such T cells in the elderly is associated with reduced functionality, lower vaccine responses, and increased risk of infection, neurocognitive problems, and cardiovascular disease.

    “The biologic impact of such T cells remains controversial, but their presence in the elderly has been associated with a decline in functionality, reduced vaccine responses, and increased risk of infection, neurocognitive problems and cardiovascular disease.”
    Quote in the paperNot a substantial claim
39 of 39

  • The paper relies on this without support.

    Telomere shortening or loss of telomeric sequence reserve reflects biological aging and can be used to estimate how much faster RA patients age.

    “Based on loss in telomeric sequence reserve, RA patients age about 25–30 years faster than non-RA controls.”

  • The paper relies on this without support.

    The mechanisms of immunosenescence are sufficiently shared across RA, HIV infection, and progeroid syndromes for evidence from one condition to illuminate the others.

    “A common denominator of physiologic aging, RA and HIV infection is the co-occurrence of immune deficiency, smoldering inflammation and tissue degeneration.”

  • The paper relies on this without support.

    DNA replication is inefficient at chromosomal ends, so replicative stress causes telomeric sequence loss.

    “Replicative stress inevitably leads to loss of telomeric sequences as DNA replication is inefficient at the chromosomal ends.”

  • The paper relies on this without support.

    Telomeres shorten by approximately 50 base pairs per cell cycle.

    “It is estimated that each cell cycle shortens telomeres by about 50 bp.”

  • The paper relies on this without support.

    Human T cells lose roughly 2000 base pairs of telomere length between ages 20 and 70, corresponding to about 40 division cycles.

    “Human T cells lose about 2000 bp between the age of 20 and 70 years, equivalent to about 40 division cycles.”

  • The paper relies on this without support.

    T cells can increase telomerase activity to extend their telomeric reserve.

    “To extend their telomeric reserve, T cells are able to upregulate the activity of telomerase.”

  • The paper relies on this without support.

    DNA breaks or chemical modifications can cause mutations and eventually malignant cell growth.

    “Breaks or chemical alterations of the DNA endanger cells as they may give rise to mutations and eventually malignant cell growth.”

  • The paper relies on this without support.

    Cells have effective machinery for recognizing and repairing DNA damage.

    “Accordingly, cells possess highly effective machineries to recognize and repair DNA damage.”

  • The paper relies on this without support.

    Genotoxic DNA lesions recruit DNA damage sensing proteins that activate signaling pathways to repair breaks and exchange altered bases.

    “DNA lesions resulting from genotoxic events recruit DNA damage sensing proteins that subsequently mobilize signaling pathways to repair breaks and exchange chemically altered bases.”

  • The paper relies on this without support.

    Many progeroid syndromes are nuclear instability syndromes caused by mutations in DNA repair molecules.

    “Of note, many of the progeroid syndromes are nuclear instability syndromes, caused by genetic mutations in DNA repair molecules.”

  • The paper relies on this without support.

    Children with ataxia telangiectasia develop premature immune aging early in life, suffer frequent infections, are radiosensitive, and face a high risk of lymphoma.

    “Children with AT develop premature immune aging early in life, have frequent infections, are radiosensitive and have a high risk of lymphoma development.”
11 of 11

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Early studies using telomeric length and clonal expansion of CD4+CD28− end-differentiated T cells estimated that immune aging is accelerated by 2-3 decades in RA patients compared to age-matched controls.

    “Early studies, utilizing measurements of telomeric length and clonal expansion of CD4+CD28− end-differentiated T cells, estimated that the immune aging process is accelerated by 2–3 decades in patients with RA as compared to age-matched controls”

    From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Weyand et al., 2014

Cites

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Authors
Weyand, C. M., Yang, Z., & Goronzy, J. J.
Affiliations
VA Palo Alto Health Care System (US)
Corresponding author
Weyand, Cornelia M.
ORCID
Venue
Current Opinion in Rheumatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2014-01
Volume
26
Issue
1
Pages
93-100
ISSN
1040-8711 (ISSN-L)
DOI
10.1097/bor.0000000000000011
PMC
PMC3984035
OpenAlex
W2319499451
Semantic Scholar
18460c795e1ed7341912c5507c4d96ff4d269dd2
Cited by
164
References
76
Citations by year
2026: 7 · 2025: 17 · 2024: 9 · 2023: 10 · 2022: 11 · 2021: 23 · 2020: 22 · 2019: 13 · 2018: 11 · 2017: 13 · 2016: 10 · 2015: 17 · 2014: 1
FWCI
1.03
Type
journal article
Language
en
Open access
Locations
  • Current Opinion in Rheumatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (R01AG045779, AG045779)
  • National Heart, Lung, and Blood Institute (R01HL063919, P01HL058000, HL-058000)
  • National Eye Institute (EY011916, R01EY011916)
  • National Institute of Allergy and Infectious Diseases (AI090019, R01AI108906, R56AI044142, U19AI090019, AI057266, R01AI108891, U19AI057266)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR042527, R01AR042527)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
Keywords
T cell senescence, immunosenescence, rheumatoid arthritis, senescence-associated secretory phenotype, chronic inflammation, DNA repair, telomere uncapping, genomic stress, T cell signaling, chronic HIV infection, tissue microenvironment
MeSH terms
Aging, Arthritis, Rheumatoid, DNA Damage, DNA Repair, Humans, T-Lymphocytes, Cellular Senescence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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